Alkoxy-1,2,3-benzotriazine-4(3h)-ones 3 - (alpha-substituted amino-beta-alkoxybenzoxypropyl)-6,7- or 6,7,8-

ABSTRACT

THE PRESENT INVENTION PERTAINS TO NEW, PHARMACOLOGICALLY VALUABLE BASICALLY SUBSTITUTED 1,2,3-BENZOTRIAZINE4(3H)-ONE DERIVATIVES HAVING EXCELLENT CORONARY DILATORY PROPERTIES AND WHICH HAVE THE STRUCTURAL FORMULA   4-(O=),3-((R2)M-C6H4-COO-CH(-CH2-R&#39;&#39;)-CH2-),(R1)N-3,4-   DIHYDRO-1,2,3-BENZOTRIAZINE   WHEREIN R&#39;&#39; IS A RADICAL SELECTED FROM THE GROUP CONSISTING OF N-METHYLPIPERAZINO, N-PHENYPIPERAZINO AND N-TRIMETHOXYBENZOXYETHYLPIPERAZINO, SAID RADICAL BEING BOUND VIA A NITROGEN ATOM; R1 IS A LOWER ALKOXY GROUP HAVING 1-4 CARBON ATOMS WHICH MAY BE IN THE 6,7 OR 6,7,8-POSITION; R2 IS AN ALKOXY HAVING 1-4 CARBON ATOMS; M IS AN INTEGER SELECTED FORM 1,2 AND 3; AND N IS AN INTEGER SELECTED FROM THE GROUP CONSISTING OF 2 AND 3 AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.

3,757,019 3 (oz-SUBSTITUTED AMINO-fl-ALKOXYBENZOXY- PROPYL)-6,7- R6,7,8-ALKOXY-1,2,3-BENZOTRI- AZINE-4(3H)-0NES Adolf Stachel, deceased,by Ingeburg Lydia Katharina Stachel, heiress-at-law, Oifenbach-Main,Rudi Beyerle, Bruchkobel, Rolf-Eberhard Nitz, Bergen-Enkheim, and KlausResag and Eckhard Schl'aven, Frankfurt am Maiu-Fechenheim, Germany; saidBeyerle, Nitz, and Schraven assiguors to Cassella Farbwerke MainkurAktiengesellschaft, Frankfurt am Main-Fechenheim, Germany No Drawing.Original application May 18, 1970, Ser. No. 38,544, now Patent No.3,706,739. Divided and this application June 22, 1972, Ser. No. 265,249Claims priority, application Germany, May 22, 1969, P 19 26 075.4 Int.Cl. C07d 55/08 US. Cl. 260-248 AS 4 Claims ABSTRACT OF THE DISCLOSUREThe present invention pertains to new, pharmacologically valuablebasically substituted 1,2,3-benzotriazine- 4(3H)-one derivatives havingexcellent coronary dilatory properties and which have the structuralformula wherein R is a radical selected from the group consisting ofN-methylpiperazino, N-phenylpiperazino andN-trimethoxybenzoxyethylpiperazino, said radical being bound via anitrogen atom; R is a lower alkoxy group having 14 carbon atoms whichmay be in the 6,7 or 6,7,8-position; R is an alkoxy group having 14carbon atoms; m is an integer selected from 1, 2 and 3; and n is aninteger selected from the group consisting of 2 and 3 andpharmaceutically acceptable acid addition salts thereof.

The present invention relates to new, pharmacologically valuablebasically substituted 1,2,3-benzotriazine-4(3H)- one derivatives havingthe general formula I (Rz)m wherein R is a radical selected from thegroup consisting of a secondary aliphatic, cycloaliphatic, araliphaticamine having 2 to carbon atoms or of a 5, 6 or 7-membered heterocyclicnitrogen base, which contains in the nucleus besides the nitrogen atom acorresponding number of methylene groups as well as a further nitrogenatom, an O or an S atom, said radical being bound via a nitrogen atom,

United States Patent 0 3,757,019 Patented Sept. 4, 1973 "ice R standsfor lower alkoxy groups having 1 to 4 carbon atoms which may be in the6,7 or 6,7,8-position,

R represents alkoxy having 1 to 4 carbon atoms,

In stands for the integers 1, 2 or 3 and n means the integers 2 or 3.

Furthermore, the present invention relates to processes for theproduction of said compounds.

The present application is a division of our United States Ser. No.38,544, filed May 18, 1970, now US. Patent No. 3,706,739.

The radical of a secondary amine R which is bound via a nitrogen atommay derive in the aliphatic series from mono and diamines, such asdialkylamines, alkylalkenylamines, alkylenediamines, hydroxyalkylaminesand alkoxyalkylamines.

Such amines are for instance: dimethylamine, diethylamine,allylmethylamine, N,N-diethyl-N-methylethylenediamine, N,Ndiethyl-N'-methylpropylenediamine, N- methylethanolamine,N-methylpropanolamine, N-isopropylethanolamine, N-butylethanolamine,N-benzylethanolamine, N-methylmethoxypropylamine, Nmethylethoxypropylamine.

Cycloaliphatic amines may be for instance: N-methylcyclopropylamine,N-methylcyclohexylamine.

Amines of the araliphatic series may be for instance:phenalkylalkylarnines such as benzylmethylamine, phenethylmethylamine.

Heterocyclic nitrogen bases may be for instance: 5, 6 and 7-memberedheterocyclic nitrogen bases such as pyrrolidine, morpholine,thiomorpholine, piperidine, N-methylpiperazine, N-phenylpiperazine,N-(fi hydroxyethyl)- piperazine, N-(y-hydroxypropyl)-piperazine,hexamethyl- 611611111118.

The 1,2,3-benzotriazine-4(3H)-one derivatives of the present inventionare obtained by (a) acylating, optionally in the presence of anacid-binding agent, l,2,3-benzotriazine-4(3H)-one derivatives of thegeneral formula 0 N CH CH OH R (R1), l

N OH W wherein R, has the above-given meaning, R is identical with R or,in case R' contains an acyloxy radical of the general formula said R mayrepresent the residue of the underlying hydroxy compound, with an alkoxybenzoic acid of the general formula or a functional derivative thereof,or

with nitrous acid.

electrode of the Gleichmann-Liibbers type (see U. Gleichman and D. W.Luebbers Die Messung des Sauerstoifdruckes in Gasen und Fliissigkeitenmit der Platin-Elektrode unter besonderer Beriicksichtigung der Messungim Blut, Pfliigers Arch. 271, 431-455 (1960)). The heart rate wascontinuously measured by electronic methods from systolic peaks of thearterial blood pressure. The arterial blood pressure was measured in theknown manner in the femoral artery with the aid of an electromanometerof the Statham-strain-gauge type.

The following table gives the results of the pharmacologicalinvestigations which were carried through. The preparations were testedin the form of their respective hydrochlorides:

Maximal increase in oxygen tension in the Maximal change in the LD5coronary veinous Maximal change blood pressure (sysg. lkg. Dosage, bloodin in the heart rate intolic/diastolic) in mouse mg./kg.

Preparation i.v. i.v. Percent Minutes Percent Minutes Percent Minutes3-[a-morpholino 3-(3,4,5-trimethoxybenzoxy)-propy1]-6,7 8-

trimethoxy-1,2,3-benzotn azine-4(3H)-one 0. 2 0. 5 +106 25 19 25 43/-3225 3-[a-(4-fl-3,4,5-trimethoxybenzoxyethyl-piperazino) -B-(3,4,5

trimethoxybenzoxy) -propyl]-6,7,8-trimethoxy-1,2,3-benzotriazine-4(3H)one 0. 25 0. 5 +109 60 -5 22/31 603-[a-morpho1ino-fi-(3,S-dimethoxybenzoxy) -propyl]-6,7,8- 0. 0. 5 +57 15+23 15 -25/ 19 15 trimethoxy-l ,2-3-benzotriazine-4(8H)-one3-[a-morpholino-fl-(3,5-dimethoxy-4-n-butoxybenzoxy) -propyl]-6,7.8-trimethoxy-1 ,2,3-benzotriazine-4(3H)-one 0. 4 0. 5 +55 40 0 4032/ -25 35 3-[a-piperidino-B-(3,4,5-tflmethoxy-benzoxy) -propyl]-6,7,8-0. l 0. 5 +25 35 5 35 +6/ 12 15 trimethoxy-1,2,3-benzotriazine-4(3H)-one a-[a-hexamethyleneimino 8- (3 ,4,5,trlmethoxybenzoxy) -propyl]6,7,8-trimethoxy-1,2,3-benzotriazine-4(3H)-one 0. 13 0. 5 +19 -12 30-4/18 20 3-[11-(4'-methylpiperazino)-B-(3,4,5-trimethoxybenzoxy)propyl]6,7-8-trimethoxy-1,2,3-benzotrlazine-4(3H) -one 0. 24 2. 0 +65 655 65 -7/ -14 15 3-[a-(4-phenylpiperazino)-B-(3,4,5-trimethoxybenz0xy) 0.25 0. 5 +17 15 3 15 -4/ 6 15propyl]-6,7,8-trimethoxy-l,2,3-benzotriazine-4(3H)-one.3-[a-pyrrolidino-B-(3,4,5-trimethoxybenzoxy) -propyl]-6,7,8

trimethoxy-l,2,3-benzotriazine-4(3H)-one 0. 043 0. 5 +79 80 11 80 =l=03-[a-(N-methyl-N-a-methoxypropylamino)B-(8,4,5-trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy-1,2,3-benzotriazine- 4(3H)-nne 0. 5 +138 240--13 -35/3fi 35 3-[a-(N-methyl-N-a-diethylami nopropylamino)-8-(3,4,5-trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy-1,2,3-beuzotriazine-4(3H)-0ne0.028 2. 0 +267 155 15 155 51/48 1553-[a-(N-methyl-N-benzylamino)-fl-(3,4,5-trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy-1 ,2,3-benz0tri azine-4 (3H)-one 0. 17 0. 5+128 70 21 70 -27/ 35 70 If, according to the process described underpara. (a), initial products are used wherein the radical of an amine R,which is bound via a nitrogen atom, contains a hydroxyalkyl group, andif 2 mols of alkoxy benzoic acid or of a functional derivative thereofare employed, one obtains the corresponding diesters. The 3-(' -amino-3-hydroxypropyl)-1,2,3-benzotriazine-4(3H)-ones required as startingmaterial may be obtained by various ways of preparation according to theteachings of the corresponding application having the same title and thesame filing date.

The initial products required for the process described under para. (b)may be prepared inthe usual manner according to known per se processes.The nitrous acid which causes the cyclization is formed in an acidreaction medium from the alkali metal nitrites employed.

The 1,2,3-benz0triazine-4(3H)-one derivatives of the present inventionare valuable pharmaceuticals. In particular, they are excellent coronarydilators and, in this respect, superior to other known substances ofthis kind.

With respect to the change in the oxygen tension in the coronary veinousblood, the pharmacological investigation of the vasodilator action onthe coronary vessels was carried out in dogs according to the methodsdescribed by W. K. A. Schaper and his co-workers (see W. K. A. Schaper,R. Xhonneux, and I. M. Bogaard Uber die kontinuierliche Messung desSauerstoifdruckes im venosen Coronarblut (Naunyn-Schmiedebergs Arch.exp. Path. u. Pharmak. 245 (383-389 (1963)). The test preparations wereapplied intravenously to the narcotized and spontaneously breathinganimals. On these test conditions the dilatation of the coronaryarteries caused by the test substances along with the increase in thecoronary blood flow led to an increase in the oxygen tension in thecoronary veinous blood. This oxygen tension was measured according topolarographic methods by means of a platin For a better understanding ofthe nature and the objects of this invention, reference should be madeto the accompanying examples which are of an illustrative rather than alimiting nature. Unless otherwise stated, all temperatures given are indegrees centigrade.

38.0 g. (0.1 mol) 3-('y-morpholino-p-hydroxy-propyl)-6,7,8-trimethoxy-1,2,3-benzotriazine-4(3H)-one are dissolved in 250 cc.anhydrous benzene and 11.1 g. (0.11 mol) triethylamine are added.Subsequently, a solution of 25.3 g. (0.11 mol) 3,4,5-trimethoxybenzoylchloride v in cc. anhydrous benzene are added dropwise while obtains the3-['y-morpholino-B-(3,4,5-trimethoxybenzoxy) propyl] 6,7,8trimethoxy-l,2,3-benzotriazine-4 (3H)-one in the form of colorlesscrystals having a melting point of 142-144". Yields: 48 g. (=84% of thetheoretical EXAMPLE 2 O CH (i) CH: I

CH;O O CH:

49.6 g. (0.1 mol) 3-['y-(4'-fi-hydroxyethylpiperazino [l']) ,8hydroxy-propyl]-6,7,8-trimethoxy-1,2,3-benzotriazine-4(3H)-onedihydrochloride are dissolved in 500 cc. anhydrous chloroform with theaddition of 40.4 g. (0.4 mol) triethylamine. A solution of 46 g. (0.2mol) 3,4,5-trimethoxybenzoyl chloride in 150 cc. anhydrous chloroform isadded dropwise while stirring within 1 hour. After the decay of theexothermic reaction stirring is continued for another 2 hours at -50.The thusly obtained reaction mixture is first washed several times withwater,

then with a 10% aqueous sodium bicarbonate solution and 30 again withwaterhSubsequently, the solvent is distilled offthoxybenzoxyethylpiperazino1']-B-3,4,5trimethoxybenzoxy-propyl]-6,7,8-trimethoxy-1,2,3-benzotriazine4(3H)- one in the form of colorless crystals decomposing'at 150. Yield:g. (=79% of the theoretical) Analogously to the description given inExamples 1 and 2 the following compounds of the present invention may beprepared:

General formula:

at 40 1n the wateret vacuum and the residue, a light NCH CHCH R yellowoil, is dissolved, for further purification purposes, I in diluteaqueous hydrochloric acid. This solution is l extracted with ether andfiltered in order to become 35 (I34) limpid. By the addition ofpotassium carbonate until the reaction mixture shows an alkalinereaction (pH 9), the R diester being formed separates in the form of acolorless oil. It is extracted with ethyl acetate which is washedMelting point (hydrochloride), On 2)m R degrees 6,7,8-(OCH3): (|)CH3 1256,7,8-(0CH3); GH: Same as above -o coclm OCH:

6,7,8'(O CH3): '0 C3H5 -N (CzHa)! 200-202 -o c-Qo 02H:

OC2H5 6,7,8-(OCHa): OC N(Ca 5). 208-210 -oc--oorn 6,7,8-(0CH Same asabove 190 6,7,8-(OCH3): d0

6,7,8-(0CH) ...do

a 3 --N N-om 6,7,8 (OCH3)3 do 1 1 3 -N N-CqH 2-nitro-3,4,5-trimethoxy-N--diethylamino-phydroxypropyl -benzamide 82.6 g. (0.3 mol)2-nitro-3,4,5-trimethoxybenzoyl chloride are dissolved in 200 cc.anhydrous benzene and added dropwise, while stirring, to a solutionconsisting of 43.8 g. (0.3 mol) 'y-diethylamino-B-hydroxypropylamine and30.3 g. (0.3 mol) triethylamine in 500 cc. anhydrous benzene. Stirringis continued for 3 hours under reflux and after cooling down, thefiltrate is evaporated to dryness in vacuo. For further purificationpurposes the crude product is dissolved in dilute hydrochloric acid and,after filtration, the filtrate is rendered alkaline by the addition ofan aqueous potassium carbonate solution. The base which hereby separatesin the form of an oil, is dissolved in ethyl acetate and washed severaltimes with water. After drying over potassium carbonate the ethylacetate solution is concentrated in vacuo and thus obtained is theZ-nitro- 3,4,5-trirnethoxy-N-('y-diethylamino B hydroxypropyl)-benzamide in the form of a yellowish oil. Yield: 91 g. (=79% of thetheoretical).

2-nitro-3,4,5-trimethoxy-N- ['y-diethylamino-fi-( 3,4,5

trimethoxybenzoxy)-prpyl]-benzarnide 38.5 g. (0.1 mol)2-nitro-3,4,5-trimethoxy-N-(' -diethylamino-p-hydroxypropyl)-benzamideand 15.15 g. (0.15

7 TABLECont1nued 8 Melting (hg l (R1). (R2)... R ESQ 1 :35

6,7,8-(OCH3)3 ....d0 N/ 6,7,8-(0 CH3)3 0 CH CH 130 0 C I OCHa -lICH2CH:CH:O-CH

6,7,8(OCH Same as above CH3 75 I I-CHr-OHiCH2N 2 5):

, 6,7,8-(OGHg); ..d0 CH; 75 I ICH2-CcH5 6,7,8-(001193 -..d0 CH3 II--CHa-CH=CH:

6,7,8(OCH )3 "d0 CH3 85 1q- H 6,7,8--(OCH3)a ..d0 CH:

CH: --I ICH 6,7-(OCH3): b 136-138 (m-(00113), ..d0 22o 6,7-(OCHah d0N(C2H5)2 105 v- 0on3). --do CH; 180

-I ICHaCH=CH3 6,7-(0GH3), --do CH3 1 165 -I I-CHaCH2CHaN(C2H )z6,7-(OCHa): d0 O CH; l 192 --I{\ N-CH2CHzOOC OCH3 1 Dihydroehlorlde.

EXAMPLE 3 mol) triethylamine are dissolved in 200 cc. anhydrous benzeneand admixed with stirring with a solution consisting of 34.5 g. (0.15mol) 3,4,5-trimethoxybenzoyl chloride in cc. anhydrous benzene.Subsequently, the reaction mixture is heated to the boil and stirring iscontinued for 6 hours under reflux. After cooling down the reactionproduct is stirred out with 300 cc. water and the benzene layer isseparated. Subsequently, the benzene layer is shaken out with dilutehydrochloric acid. The aqueous hydrochloric acid solution is renderedalkaline by the addition of aqueous potassium carbonate solution and thebase which separates in the form of an oil is dissolved in ethylacetate. The thusly obtained ethyl acetate solution is washed with waterand evaporated to dryness, after drying over potassium carbonate, invacuo. For further purification the crude product is recrystallized fromalcohol. Thus obtained is the 2-nitro-3,4,5-trimethoxy-N-['ydiethylamino3 (3,4,5 trimethoxybenzoxy)-propyl]- benzamide in the form of lightyellow crystals melting at 107. Yield: 46 g. (-=79.5% of thetheoretical).

2-amino-3,4,5-trimethoxy-N-['y-diethylamino-fi-(3,4,5-trimethoxybenzoxy) -propyl] -benzam'ide 58 g. (0.1 mol)2-nitro-3,4,5-trimethoxy-N-['y-diethylamino-,B-(3,4,5-trimethoxybenzoxy)-propyl]I benzamide are dissolved in 250 cc. methanol and hydrogenated at 30-40in the presence of Raney nickel at a hydrogen pressure of 70atmospheres. The reaction product is sucked oil from the catalyst andthe filtrate is evaporated to dryness in vacuo. The oily residue isdissolved in ethyl acetate and by the addition of etheric hydrochloricacid the dihydrochloride of the 2-amino-3,4,5-trimethoxy N-['y-diethylamino p (3,4,5-trimethoxybenzoxy)-propyl]- benzamide isprecipitated in the form of colorless needles having a decompositionpoint of 75. Yield: 49 g. (=78.7% of the theoretical).

3- diethylamino-fi- (3 ,4,5-trimethoxybenzoxy) -propyl]6,7,8-trimethoxy-1,2,3,-benzotriazine-4(3H)-one 31 g. (0.05 mol)2-amino-3,4,5-trimethoxy- N-['y-diethylamino-fl-(3,4,5-trimethoxybenzoxy) propyl] benzamidedihydrochloride are dissolved in 100 cc. water and at 0-5 admixeddropwise while stirring and cooling with a solution consisting of 3.5 g.(0.05 mol) sodium nitrite in 20 cc. water. Stirring is continued for 2hours at 0-5, then the temperature is allowed to reach room temperature.After having stirred overnight, the reaction mixture is rendered neutralby the addition of aqueous sodium bicarbonate solution and the reactionproduct that precipitates in the form of crystals is sucked Oil. Forfurther purification purposes it is then recrystallized from methanol.Thus obtained is the 3-[7-diethylamino-B-(3,4,5-trimethoxybenzoxy)propyl]-6,7,8-trimethoxy-l,2,3-benzotriazine-4(3H)-one in the form ofcolorless needles" melting at 92-95. Yield: 22 g. (=78.6% of thetheoretical).

What is claimed is:

1. A compound having the structural formula wherein R is a radicalselected from the group consisting of N-methylpiperazino,N-phenylpiperazine and N-trimethoxybenzoxyethylpiperazino, said radicalbeing bound via a nitrogen atom; R is a lower alkoxy group having 14carbon atoms which may be in the 6, 7 or 6,7,8-position; 'R is an alkoxygroup having 1-4 carbon atoms; m is an integer selected from 1, 2 and 3;and n is an integer selected from the group consisting of 2 and 3 andpharmaceutically acceptable acid addition salts thereof.

2. 3-[7-(4' B 3,4,5trimethoxybenzoxyethylpiperazino)-fl-(3,4,5-trimethoxybenzoxy)-propyl]6,7,8 trimethoxy-1,2,3-benzotriazine-4(3H)-one and pharmaceuticallyacceptable acid addition salts thereof.

3. 3-['y-(4'-methylpiperazino) 3(3,4,5-trirnethoxybenzoxy)-propyl]-6,7,8-trimethoxy 1,2,3 benzotriazine-4(3H)-one and pharmaceutically acceptable acid addition salts thereof.

4. 3-['y-(4'-phenylpiperazino) B (3,4,5-trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy 1,2,3 benzotn'azine- 4(3H)-one and pharmaceuticallyacceptable acid addition salts thereof.

References Cited FOREIGN PATENTS 1,926,076 12/1970 Germany.

JOHN M. FORD, Primary Examiner U.s. c1. X.R. 424249

